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Unmasking a cellular hallmark of cancer

Discovery points to precise therapies targeting the cell membrane

Cancer is tough to beat because it hijacks the very genes and signaling pathways that control normal tissue growth and cellular function. Any cancer therapy that attempts to beat the disease by targeting these genes and signals inevitably affects healthy tissue.

This week, scientists at the UCSF School of Pharmacy unveiled new research that promises to make it easier to distinguish several types of cancerous cells from healthy cells. The team showed that a signaling pathway called RAS, known to play a prominent role in a third of malignant cancers, uniquely alters the array of proteins dotting the cell membrane during cancer. The findings, published in the journal eLife, provide a necessary new avenue not just for the study of cancer but also for delivering drug therapies that target only cancer cells.

“More studies in this area would help us understand how mutations in RAS signaling drive malignancy, and may point to novel targets for antibody and cellular-therapy-based treatment in RAS-driven cancers,” senior author James Wells, PhD, told UCSF News.
 

Schematic of antibodies delivering cancer therapies to a tumor cell

By linking a cancer drug to a series of antibodies that stick to CDCP1, researchers ensure delivery of the drug to cancer cells alone.

Wells is a faculty member in the School’s Department of Pharmaceutical Chemistry and a member of the Helen Diller Family Comprehensive Cancer Center at UCSF. He holds the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences at UCSF.

While mutations in RAS have long been known to cause cancer, therapies that block RAS signaling aren’t very useful for fighting cancer. That is because the pathway has a hand in numerous processes that are vital for cellular health.

Wells and his team used a technique called mass spectrometry to tentatively identify all of the proteins present on the surface of cancer cells that were expressing a mutant version of RAS. They next developed a suite of antibodies that would stick to seven of these proteins, confirming that five of the proteins were actually present on the membranes of cancerous cells.

In a related experiment, one of these surface proteins, CDCP1, was also found to be vital for relaying some of the cancer-causing signals that were triggered by mutant RAS. The researchers then showed that an antibody that attaches exclusively to CDCP1 could be used to guide anti-cancer drugs directly to cancerous cells.

“Overall, we've presented a novel technological pipeline for the discovery and application of antibodies to surface proteins regulated by cancer-causing signaling pathways,” Wells said. “Ultimately, we hope this pipeline can be used to attack undruggable targets, including RAS, from the outside.”

Additional authors on the study included Alexander J. Martinko; Charles Truillet, PhD; Olivier Julien, PhD; Juan Diaz, PhD; Max A. Horlbeck; Jonathan S. Weissman, PhD; Sourav Bandyopadhyay, PhD; and Michael Evans, PhD; all of UCSF; with Gordon Whiteley, PhD, and Josip Blonder, MD, of the Frederick National Laboratory for Cancer Research.

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About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.

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